Cold sores are liquid-filled blisters that erupt around the lips and sometimes spread to the nose, chin, eyes, and the skin of the fingers. Cold sores are caused by the herpes simplex virus, type 1 (HSV-1). There are two types of the herpes simplex virus: type 1 (HSV-1), which causes oral herpes and type 2 (HSV-2), which causes genital herpes. Oral herpes manifests itself as cold sores, which are also known as fever blisters.
Most people are infected with HSV-1 by the time they are 10-years-old. Studies in the United States indicate that 30 to 60 percent of children under the age of 10 years have been exposed to HSV-1. The incidence of infection steadily increases with age, reaching 80 to 90 percent among adults 50 years of age and older. Eighty percent of all Americans have the virus that causes cold sores, but only 60 percent have experienced an outbreak. Nearly a quarter of those sufferers experience recurrent outbreaks. Some people do not develop symptoms until months or even years after becoming infected with the virus, and some never experience any symptoms.
HSV-1 is an extremely contagious virus when a sore is present. The virus is spread by direct skin-to-skin contact. Unlike an airborne flu virus, herpes spreads directly from the cold sore to the site of contact. The cold sore is no longer contagious when it has completely healed and the affected skin has returned to normal. The virus usually enters the body through the mouth. The initial contact with the disease does not result in a cold sore, but can be either asymptomatic (no obvious symptoms of infection) or with symptoms more readily associated with an upper respiratory infection, and often lesions in the mouth.
The initial symptoms of an HSV-1 infection usually include burning, tingling, or itching sensations about the edges of the lips or nose within one or two weeks after contact with an infected person. Several hours later, small red papules develop in the irritated area; later small vesicles, or fever blisters, filled with fluid erupt. Several small vesicles may merge to form a larger blister. The vesicles generally are associated with itching, pain, or similar discomfort. Other effects often include a mild fever and enlargement of the lymph nodes in the neck. Laboratory analysis of the vesicular fluid usually shows the presence of herpesvirus particles and the absence of pyogenic bacteria. Within 1 week after the onset of symptoms, thin yellow crusts form on the vesicles as healing begins.
Following the initial episode, the virus moves away from the nerve endings up into portions of the nervous system close to the lips. The HSV-1 virus remains in the body for the remainder of the person's life. What causes approximately one-third of those initially infected to suffer from recurrent cold sores is unknown. However, for those individuals who do suffer from recurrent cold sores, certain factors will initiate the development of a cold sore. These factors include, e.g., colds/flu, emotional stress, fever, sunlight, cold weather and menstruation. The exact mechanism by which trigger factors induce activation of HSV-1 is unknown.
Herpes zoster or shingles is an acute infection caused by reactivation of the latent varicella zoster virus (VZV), which mainly affects adults. It is characterized by the development of painful vesicular skin eruptions that follow the underlying route of cranial or spinal nerves inflamed by the virus.
Distribution of the pain and vesicular eruptions associated with VZT is usually unilateral, although both sides of the body may be involved. Any sensory nerve may be affected, but the virus in most cases tends to invade the posterior root ganglia associated with thoracic and trigeminal nerves. The pain, which may be constant or intermittent, superficial or deep, usually precedes other effects and may mimic that of other disorders, such as appendicitis and or pleurisy. Early symptoms may include gastrointestinal disturbances, malaise, fever, and headache. The vesicles usually evolve from small red macules along the path of a nerve, and the skin of the area is hypersensitive. All of the lesions may appear within a period of hours, but they most often develop gradually over a period of days. The macules vesiculate and after about 3 days, become turbid with cellular debris. Usually at the end of the first week, the vesicles develop crusts. The symptoms may persist for 3 to 5 weeks, but in most cases they diminish after 2 weeks.
Varicella or chickenpox is an acute, highly contagious viral disease caused by a herpesvirus, varicella zoster virus (VZV). It occurs primarily in young children and is characterized by crops of pruritic vesicular eruptions on the skin. The disease is transmitted by direct contact with skin lesions or, more commonly, by droplets spread from the respiratory tract of infected persons, usually in the prodromal period or the early stages of the rash. The vesicular fluid and the scabs are infectious until entirely dry. Indirect transmission through uninfected persons or objects is rare. The diagnosis is usually made by physical examination and by the characteristic appearance of the disease. The virus may be identified by the culture of the vesicle fluid.
The incubation period for chickenpox averages 2 to 3 weeks, followed by slight fever, mild headache, malaise, and anorexia usually occurring 24 to 36 hours before the rash begins. The prodromal period is usually mild in children but may be sever in adults. The rash, which is highly pruritic, begins as macules and progresses in 1 or 2 days to papules, and finally, to vesicles surrounding an erythematous base and containing a clear fluid. Within 24 to 48 hours, the vesicles turn cloudy and become umbilicated, are easily broken, and become encrusted. The lesions, which erupt in crops so that all three stages are present simultaneously, first appear on the back and chest and then spread to the face, neck and limbs; they occur only rarely on the soles and palms. In severe cases, laryngeal or tracheal vesicles in the pharynx, larynx, and trachea may cause dyspnea and dysphagia. Prolonged fever, lymphadenopathy, and extreme irritability from pruritus are other symptoms. The symptoms last from a few days to 2 weeks.
Aphthous stomatitis or a canker sore is an ulcerous lesion of the mouth, characteristic of aphthous stomatitis. Canker sores are a recurring condition characterized by the eruption of painful ulcers on the mucous membranes of the mouth. The cause is unknown, but there is evidence to suggest that aphthous stomatitis is an immune reaction. Heredity, some foods, overenthusiastic tooth brushing, and emotional stress are also possible causes.
Cold sores or fever blisters and shingles can be treated with antiviral medications, including acyclovir, famciclovir and valacyclovir. However, these medications must be repeatedly applied to the infected areas. The medications, which are typically formulated as creams or gels, are messy, unsightly, and inconvenient to the user. In addition, the medications do not treat the symptoms (e.g., burning, tingling, or itching) or secondary infections associated with the cold sores or fever blisters. Chickenpox can be treated with topical antipruritics to relieve the itching and can be treated with antibiotics to treat secondary infections. Again, the medications, which are typically formulated as creams or gels, are messy, unsightly, and inconvenient to the user.
Smallpox is a viral disease with reported death rates in non-immune human populations of approximately 30% (U.S. Centers for Disease Control, Smallpox internet homepage, http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.as). It is caused by the variola virus (U.S. Centers for Disease Control, Smallpox internet homepage, http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.as). Historically smallpox caused devastating epidemics throughout the world. However, by 1977 mass immunization against smallpox eradicated the virus that causes the disease in the wild (U.S. Centers for Disease Control, Smallpox internet homepage, http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.as). Stores of virus were maintained by the United States and the Soviet Union, and possibly other nations. It is believed the virus may now be in the hands of terrorists or states that pose a military threat to the United States and to other nations. These groups and nations might unleash the virus as a weapon against soldiers or civilians. Accordingly, governments are preparing again to vaccinate at least segments of their populations and possibly the general population.
The vaccines planned for use in the United States are based on live strains of a vaccinia virus related to the variola virus that causes smallpox (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp). The vaccinia virus infects other species of mammals and generally causes a localized infection in humans that is not serious, but that results in immunity to smallpox (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp). One such vaccine is DRYVAX™, which is based on vaccinia prepared from the lymph of calves infected with the virus (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/about_vaccine.htm). To administer the vaccine, a bifurcated needle is dipped in a reconstituted suspension of the virus. The needle is then used to repeatedly puncture the skin of a person being vaccinated (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/vac_method.htm). If the vaccine “takes,” an immune response is elicited. The result is a papule 3-4 days after vaccination. This progresses to a vesicle with surrounding erythema by 5-6 days after vaccination. The vesicle center becomes depressed and progresses to a well-formed pustule by the 8th or 9th day. By the twelfth day or soon thereafter, the pustule crusts over forming a brown scab. After approximately 3 weeks the scab detaches and a well formed scar remains. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/normal.htm.)
Importantly, alcohol cannot be applied to the skin prior to the vaccination to sterilize the skin because this has been shown to inactivate the virus. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/vac_method.htm.) Not applying alcohol has the result that the vaccinee is at greater risk that the wound caused by vaccination could be infected with infectious agents present on the skin.
The vaccinia virus infection created by vaccination causes the skin to itch (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/ery_multi_clinical.htm.). This is a problem because contact with the lesions of the skin can spread the virus to other areas of the body and to other persons. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions-vacc-public.htm.) Transfer of the virus to the eye or surrounding skin of the vaccinee or other persons is particularly dangerous, because infection with vaccinia in the eye can cause blindness (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/prevent.htm.). Thus, the vaccinee must be advised to avoid touching or rubbing the vaccination site.
Covering the vaccination site with a sterile gauze is recommended. However, the gauze must be disposed of carefully after use because it contains viable virus and can spread the infection to others or to other areas of the vaccinee. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/vac_method.htm.)
The most severe risk associated with vaccination is progressive vaccinia. This occurs in approximately 1-10 persons per 1 million receiving vaccination. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/prog_vac.htm.) The virus multiplies at the primary vaccination site causing circumferential expansion of the skin lesion at the site. The virus gains entry to the blood and spreads to distant skin sites and multiple organs. Local and systemic bacterial, fungal, and parasitic infections can ensue. Death caused by toxic or septic shock is likely. (U.S. Centers for Disease Control, smallpox vaccination page,
http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/prog_vac_path.htm.) Patients must be hospitalized and are treated with aggressive immunoglobulin therapy. The risk of progressive vaccinia is greater in immune compromised individuals, such as HIV infected persons and cancer patients (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/prog_vac_path.htm).Accordingly, immune compromised persons should not receive the smallpox vaccine. However, the possibility of transfer of the virus from vaccinees to others still places immune compromised persons at risk from the vaccine.
A more common risk of vaccination is bacterial infection at the site of vaccination (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/bac_inf.htm). Staphylococci and streptococci infections are the most likely. Normal skin flora includes staphylococcal and streptococcal species. In addition, in infants fecal contamination of the skin is common. Thus, disruption of the skin by vaccination may provide a fertile field for bacterial superinfection and multiplication (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/bac_inf.htm). The use of occlusive dressings over the site of vaccination can increase this risk. Tightly bound and occlusive dressings can macerate the skin. They also may lead to more frequent occurrence of infection, anaerobic infection, and more serious disease. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/bac_inf.htm.)
Another common side effect of vaccination is generalized vaccinia, which is a benign spreading of the virus through systemic circulation, which leads to lesions on unimmunized skin (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/gen_vac_clinical.htm).
Another adverse event associated with vaccinia vaccination is erythema multiforme, which is a toxic or allergic skin rash that can be frightening in appearance. Intense itching can accompany the rash, and scratching can lead to bacterial superinfection. Rarely, erythema multiforme develops into desquamating Stevens-Johnson syndrome with full body involvement and conjunctival and corneal inflammation. (U.S. Centers for Disease Control, smallpox vaccination page, http://www.bt.cdc.gov/training/smallpoxyaccine/reactions/ery_multi_clinical.htm)
Hence, methods to treat side effects and adverse events associated with smallpox vaccination are needed. A need exists for treatments to reduce itching and scratching associated with the vaccination, and to prevent or treat superinfection with bacterial, viral, and fungal infectious agents at the vaccination site. A need also exists for treatments to reduce the risk of spreading the vaccinia infection to other persons, or other areas of the body, including the eyes and surrounding skin.
Several topical patch devices have been used for applying medication to the skin. For example, U.S. Pat. No. 4,675,009; U.S. Pat. No. 5,536,263; and U.S. Pat. No. 5,741,510 each describe a drug dispensing device for the delivery of medication to the skin. While the patches disclosed are generally effective in the delivery of a medicament (e.g., topical antitussive) to the skin, there exists a need for water insoluble, protective, adhesive patches that administer effective and known amounts of an antiviral agent, external anesthetic or analgesic, antipruritic, and antimicrobial agent to the skin. The suitable patch should maintain the adhesive properties of the patch and the stability of one or more of the antiviral agent, external anesthetic, analgesic, antipruritic, and antimicrobial agent over a prolonged period of time typically experienced in the manufacturing, packaging, shipping, and/or the storage of the patch (e.g., up to about two years). The suitable patch should be effective in treating cold sores or fever blisters. The suitable patch should also be effective in preventing secondary infections associated with cold sores or fever blisters. In addition, the suitable patch should treat the symptoms (e.g., burning, tingling, or itching) associated with the cold sores or fever blisters. Preferably, the patch will comply with any FDA regulations regarding the one or more of the antiviral agent, external anesthetic, analgesic, antipruritic, and antimicrobial agent. The suitable patch should also administer an effective and known amount of one or more of the antiviral agent, external anesthetic, analgesic, and antipruritic to the skin of the patient.